Phenocopies of primary immunodeficiency

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Immunodeficiency Affecting Cellular and Humoral Immunity

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Predominantly Antibody Deficiency

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Phenocopies of Primary Immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2], Anmol Pitliya, M.B.B.S. M.D.[3]

Overview

Classification

 
 
 
 
Phenocopies of PID
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Associated with Somatic Mutations
 
 
 
 
Associated with Auto-Antibodies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALPS-SFAS
 
 
 
 
 
Chronic mucocutaneous candidiasis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RALD(RAS-associated autoimmune leukoproliferative disease)
 
 
 
 
 
Adult-onset immunodeficiency with susceptibility to mycobacteria
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cryopyrinopathy(Muckle-Wells Syndrome)
 
 
 
 
 
Recurrentt skin infections
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypereosinophilic syndrome due to somatic mutations in STAT5b
 
 
 
 
 
Pulmonary alveolar proteinosis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acquired angiooedema
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Atypical Hemolytic Uremic Syndrome
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thymoma with hypogammaglobulinemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ALPS-SFAS

  • Heritable disorder of apoptosis, resulting in the accumulation of autoreactive lymphocytes.[1]
  • Manifests in early childhood as nonmalignant lymphadenopathy with hepatosplenomegaly and autoimmune cytopenias.[1]
  • Patients with mutations have developed B and T-cell lymphomas.[2]
  • Peripheral blood analysis in patients has demonstrated hypergammaglobulinemia along with increased numbers of B and T lymphocytes.[3]
  • Some studies have demonstrated that ALPS is compatible with long-term survival.[4][5]

Types of mutation

  • Type IA is caused by heterozygous mutation in the FAS gene (TNFRSF6, or CD95)
  • Type Ib is caused by heterozygous mutation in the FAS ligand (FASL) gene (TNFSF6 or CD95L)

RALD(RAS-associated autoimmune leukoproliferative disease)

  • Originally considered a subtype of RAS due to the significant overlap.[6][7]
  • A leukoproliferative disorder characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia.[6][7]
  • Some patients have recurrent infections with increased risk of hematologic malignancy.[6][7]

Mutated genes

  • NRAS and KRAS

Cryopyrinopathy(Muckle-Wells Syndrome)

  • Caused by heterozygous mutation in the gene encoding cryopyrin (NLRP3) and the locus identified at chromosome 1q44.[8][9]
  • Characterized by episodic skin rash, arthralgias, and fever associated with late-onset sensorineural deafness and renal amyloidosis.[10]
  • Limb pains emphasized on as a feature.[11]

Hypereosinophilic syndrome due to somatic mutations in STAT5b

  • Characterized by atopic dermatitis, urticarial rash, diarrhea and eosinophilia

Chronic mucocutaneous candidiasis

  • Includes a group of rare disorders with altered immune responses, selective against Candida.[12]
  • Characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused mainly by Candida albicans.[12]
  • Can also be associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome which is driven by Mutations in AIRE (autoimmune regulator).[13][14][15]
  • High titers of neutralizing autoantibodies against IL-17 and/or IL-22 are also detected.[16]

Adult-onset immunodeficiency with susceptibility to mycobacteria

  • A disorder predominantly found in Southeast Asians.[17][18]
  • Associated with severe or disseminated infections caused by non-tuberculous mycobacteria and other opportunistic pathogens such as non-typhoidal salmonella, cytomegalovirus, varicella zoster virus and some fungi.[19][20]
  • An infection may act as an initial trigger for the production of autoantibodies with repeated infections leading to increased activity.[19][20]

Recurrent skin infections

  • Patients with recurrent staphylococcal cellulitis and subcutaneous abscesses have shown high titers of IgG1 autoantibodies against IL-6, a pleiotropic cytokine released by several important cellular lineages of the skin.[21][22]
  • The autoantibodies against IL-6 prevent the increase in CRP concentration during infection and the impaired IL-6 mediated immunity contributes to the disease development.[21]
  • Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) can also lead to cutaneous infections typically caused by Staphylococcus aureus.[23]

References

  1. ↑ 1.0 1.1 Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB; et al. (2010). "Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome". Blood. 115 (25): 5164–9. doi:10.1182/blood-2010-01-263145. PMC 2892951. PMID 20360470.
  2. ↑ Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rösen-Wolff A; et al. (2001). "The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis". Blood. 98 (1): 194–200. PMID 11418480.
  3. ↑ Sneller MC, Straus SE, Jaffe ES, Jaffe JS, Fleisher TA, Stetler-Stevenson M; et al. (1992). "A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease". J Clin Invest. 90 (2): 334–41. doi:10.1172/JCI115867. PMC 443107. PMID 1386609.
  4. ↑ Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB (1996). "Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity". N Engl J Med. 335 (22): 1643–9. doi:10.1056/NEJM199611283352204. PMID 8929361.
  5. ↑ Canale VC, Smith CH (1967). "Chronic lymphadenopathy simulating malignant lymphoma". J Pediatr. 70 (6): 891–9. PMID 4165068.
  6. ↑ 6.0 6.1 6.2 Oliveira JB (2013). "The expanding spectrum of the autoimmune lymphoproliferative syndromes". Curr Opin Pediatr. 25 (6): 722–9. doi:10.1097/MOP.0000000000000032. PMC 4435794. PMID 24240292.
  7. ↑ 7.0 7.1 7.2 Niemela JE, Lu L, Fleisher TA, Davis J, Caminha I, Natter M; et al. (2011). "Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis". Blood. 117 (10): 2883–6. doi:10.1182/blood-2010-07-295501. PMC 3062298. PMID 21079152.
  8. ↑ Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001). "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome". Nat Genet. 29 (3): 301–5. doi:10.1038/ng756. PMC 4322000. PMID 11687797.
  9. ↑ Cuisset L, Drenth JP, Berthelot JM, Meyrier A, Vaudour G, Watts RA; et al. (1999). "Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44". Am J Hum Genet. 65 (4): 1054–9. doi:10.1086/302589. PMC 1288238. PMID 10486324.
  10. ↑ Dodé C, Le Dû N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G; et al. (2002). "New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes". Am J Hum Genet. 70 (6): 1498–506. PMC 379138. PMID 11992256.
  11. ↑ Black JT (1969). "Amyloidosis, deafness, urticaria, and limb pains: a hereditary syndrome". Ann Intern Med. 70 (5): 989–94. PMID 5769632.
  12. ↑ 12.0 12.1 Zuccarello D, Salpietro DC, Gangemi S, Toscano V, Merlino MV, Briuglia S; et al. (2002). "Familial chronic nail candidiasis with ICAM-1 deficiency: a new form of chronic mucocutaneous candidiasis". J Med Genet. 39 (9): 671–5. PMC 1735231. PMID 12205111.
  13. ↑ Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J (1990). "Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients". N Engl J Med. 322 (26): 1829–36. doi:10.1056/NEJM199006283222601. PMID 2348835.
  14. ↑ Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M; et al. (1997). "Positional cloning of the APECED gene". Nat Genet. 17 (4): 393–8. doi:10.1038/ng1297-393. PMID 9398839.
  15. ↑ Finnish-German APECED Consortium (1997). "An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains". Nat Genet. 17 (4): 399–403. doi:10.1038/ng1297-399. PMID 9398840.
  16. ↑ Puel A, Döffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C; et al. (2010). "Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I." J Exp Med. 207 (2): 291–7. doi:10.1084/jem.20091983. PMC 2822614. PMID 20123958.
  17. ↑ Chan JF, Trendell-Smith NJ, Chan JC, Hung IF, Tang BS, Cheng VC; et al. (2013). "Reactive and infective dermatoses associated with adult-onset immunodeficiency due to anti-interferon-gamma autoantibody: Sweet's syndrome and beyond". Dermatology. 226 (2): 157–66. doi:10.1159/000347112. PMID 23652167.
  18. ↑ Pithukpakorn M, Roothumnong E, Angkasekwinai N, Suktitipat B, Assawamakin A, Luangwedchakarn V; et al. (2015). "HLA-DRB1 and HLA-DQB1 Are Associated with Adult-Onset Immunodeficiency with Acquired Anti-Interferon-Gamma Autoantibodies". PLoS One. 10 (5): e0128481. doi:10.1371/journal.pone.0128481. PMC 4444022. PMID 26011559.
  19. ↑ 19.0 19.1 Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA; et al. (2012). "Adult-onset immunodeficiency in Thailand and Taiwan". N Engl J Med. 367 (8): 725–34. doi:10.1056/NEJMoa1111160. PMC 4190026. PMID 22913682.
  20. ↑ 20.0 20.1 Browne SK, Zaman R, Sampaio EP, Jutivorakool K, Rosen LB, Ding L; et al. (2012). "Anti-CD20 (rituximab) therapy for anti-IFN-γ autoantibody-associated nontuberculous mycobacterial infection". Blood. 119 (17): 3933–9. doi:10.1182/blood-2011-12-395707. PMC 3350360. PMID 22403254.
  21. ↑ 21.0 21.1 Puel A, Picard C, Lorrot M, Pons C, Chrabieh M, Lorenzo L; et al. (2008). "Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6". J Immunol. 180 (1): 647–54. PMID 18097067.
  22. ↑ Paquet P, Piérard GE (1996). "Interleukin-6 and the skin". Int Arch Allergy Immunol. 109 (4): 308–17. doi:10.1159/000237257. PMID 8634514.
  23. ↑ Chandesris MO, Melki I, Natividad A, Puel A, Fieschi C, Yun L; et al. (2012). "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey". Medicine (Baltimore). 91 (4): e1–19. doi:10.1097/MD.0b013e31825f95b9. PMC 3680355. PMID 22751495.
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